c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis

TLDR

Mitogen‑activated protein kinase cascades, especially the highly activated c‑Jun N‑terminal kinase (JNK) in rheumatoid arthritis synoviocytes, are implicated in inflammation and tissue destruction, yet their precise role remains unclear without selective inhibitors. The study aimed to determine JNK’s function in synoviocyte biology and inflammatory arthritis using a novel selective JNK inhibitor and JNK knockout mice. The authors employed the selective JNK inhibitor SP600125 and JNK1/2 knockout mice to assess JNK’s impact on IL‑1β‑induced AP‑1 activation, collagenase expression, and joint pathology. SP600125 completely inhibited IL‑1β‑induced phospho‑Jun, AP‑1 binding, and collagenase‑3 mRNA in synoviocytes, and in vivo it markedly reduced radiographic joint damage while only modestly decreasing paw swelling, confirming JNK’s essential role in collagenase expression and joint destruction and highlighting it as a therapeutic target for rheumatoid arthritis.

Abstract

Mitogen-activated protein kinase (MAPK) cascades are involved in inflammation and tissue destruction in rheumatoid arthritis (RA). In particular, c-Jun N-terminal kinase (JNK) is highly activated in RA fibroblast-like synoviocytes and synovium. However, defining the precise function of this kinase has been difficult because a selective JNK inhibitor has not been available. We now report the use of a novel selective JNK inhibitor and JNK knockout mice to determine the function of JNK in synoviocyte biology and inflammatory arthritis. The novel JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) completely blocked IL-1--induced accumulation of phospho-Jun and induction of c-Jun transcription in synoviocytes. Furthermore, AP-1 binding and collagenase mRNA accumulation were completely suppressed by SP600125. In contrast, complete inhibition of p38 had no effect, and ERK inhibition had only a modest effect. The essential role of JNK was confirmed in cultured synoviocytes from JNK1 knockout mice and JNK2 knockout mice, each of which had a partial defect in IL-1--induced AP-1 activation and collagenase-3 expression. Administration of SP600125 modestly decreased the rat paw swelling in rat adjuvant-induced arthritis. More striking was the near-complete inhibition of radiographic damage that was associated with decreased AP-1 activity and collagenase-3 gene expression. Therefore, JNK is a critical MAPK pathway for IL-1--induced collagenase gene expression in synoviocytes and in joint arthritis, indicating that JNK is an important therapeutic target for RA.